Genetic Basis for Chronic Pain Conditions Discovered

Study identifies “a new genetic mechanism that influences an individual's susceptibility to develop chronic pain conditions” such as TMJD and Fibromyalgia

December 22, 2006 - CHAPEL HILL. Researchers at the University of North Carolina (UNC) at Chapel Hill have discovered that commonly occurring variations of a gene trigger a domino effect in chronic pain disorders. The finding [which kicks off a seven-year, $19 million NIH-funded research initiative*] might lead to more effective treatments for temporomandibular joint disorder (TMJD) and other chronic pain conditions.

Catechol-O-methyltransferase (COMT), an enzyme that metabolizes neurotransmitters such as epinephrine, norepinephrine, and dopamine – and that has been implicated in the modulation of persistent pain, as well as cognition and mood – is regulated by a gene, also called COMT. Previous UNC-led research showed that common genetic variants of this gene are associated with increased pain sensitivity and the likelihood of developing TMJD.

Now, the researchers have discovered that specific variants of the COMT gene can dramatically affect the secondary structure of corresponding messenger RNA - which, in turn, leads to alterations in the amount of enzyme crucial for regulating pain processing. The discovery was published in the December 22, 2006 issue of the journal Science.**

"TMJD is a complex pain condition that is frequently associated with other pain conditions such as Fibromyalgia Syndrome, chronic headaches, and Irritable Bowel Syndrome," said Dr. William Maixner, director of the Center for Neurosensory Disorders in UNC's School of Dentistry and a study co-author.

"This study has identified a new genetic mechanism that influences an individual's susceptibility to develop chronic pain conditions such as TMJD," Maixner said.

The study was conducted to understand the mechanism by which the identified genetic variants influence enzymatic activity and, ultimately, biological functions such as pain transmission. The researchers found that three major variants of COMT show significant differences in how they code for the secondary structure of messenger RNA, or mRNA. [mRNA mediates the transfer of genetic information from the cell nucleus to provide a template for protein synthesis.] The differences lead to dramatic alterations in protein expression, which substantially influences pain sensitivity in humans.

Implications for Diagnosis and Treatment
These findings are clinically important because pain conditions resulting from low COMT activity or elevated catecholamine levels are likely to be susceptible to treatment with pharmacological agents that block beta 2- and beta 3-adrenergic receptors, which mediate COMT-dependent pain signaling, or that control mRNA secondary structure.

"Elucidating the genetic mechanisms that mediate pain perception will provide new insights into how chronic pain develops and will ultimately contribute to the identification of unique markers for diagnosing clinical pain conditions, as well as provide novel targets for the development of effective individualized therapeutics for TMJD and related conditions," said Dr. Andrea Nackley Neely, a research assistant professor in the Center for Neurosensory Disorders and the study's lead author.

"These data have broad medical and evolutionary implications regarding the analysis of variants common in the human population," Nackley Neely said. "It is believed that variants leading to altered protein structure have the strongest impact on gene function. However, this study demonstrates that combinations of common genetic variants that influence mRNA secondary structure may have even stronger effects and, thus, represent another key factor responsible for disease onset and progression."

"This study provides additional evidence of a genetic, molecular and physiological basis for pain perception and human pain conditions and should help to remove the stigma associated with conditions such as TMJD and fibromyalgia," said Dr. Luda Diatchenko, an associate professor in the center and the study's chief investigator.

Other researchers were:n Dr. Inna Tchivileva, a postdoctoral research associate within the Center for Neurosensory Disorders;n Kathryn Satterfield, a former research assistant within the center;n Dr. Olex Korchynskyi, a former postdoctoral research associate within the UNC-Chapel Hill School of Medicine's Thurston Arthritis Research Center;n Dr. Sergei S. Makarov, a former associate professor at the Center for Neurosensory Disorders and the Thurston center and now president and chief executive officer of Attagene Inc.;n Dr. Svetlana A. Shabalina, a staff scientist with the National Center for Biotechnology Information.

Funding was provided by the National Institute of Dental and Craniofacial Research, National Institute of Child Health and Human Development and National Institute of Neurological Disorders and Stroke, all components of the National Institutes of Health. Additional support came from the Intramural Research Program of the National Center for Biotechnology Information.

Part One of $19 Million NIH-Funded Intiative

Other Center for Neurosensory Disorders research initiatives are currently under way that further explore the genetic basis of pain: [They continue a] seven-year, $19-million National Institute of Dental and Craniofacial Research-funded agreement involving multiple institutions and based at the center, and will follow 3,200 healthy individuals and 200 who have facial pain. Titled OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment), the study is designed to identify both environmental and genetic factors that increase an individual's susceptibility to TMJD and other chronic pain conditions.

** The article, titled “Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure,” by AG Nackley, et al., was published in the December 22, 2006 issue of the journal Science. To view an abstract and supporting materials and methods, or to purchase the full text of the article, go to http://www.sciencemag.org/content/vol314/issue5807/index.dtl#r-articles

This is an interesting article, but does it actually MEAN anything to any of us who are in pain *right now*? No. It's all well and good to read these articles regarding research that have implications for what may happen 30 years in the future, but they offer nothing in the way of pain relief in the present and certainly nothing in the way of hope for pain relief in even the *near* future such as a year from now. Therefore, the only positive outcome of these articles is that they point to an actual *physical* component to conditions such as fibromyalgia and that takes the wind out of the sails of those who would have it thought that FMS sufferers are a bunch of "hysterics" or "malingerers". And we can certainly use that type of back up.
Thank you for adding this component, FINALLY, to ImmuneSupport.com so that one may have the opportunity to respond to these postings. This is a long-overdue option!
Sincerely,
L. Waugh, RN

Thank you to the researchers who conducted this research, and to those who founded this research.
I am 38, and have suffered chronic daily headaches since I was 18. I was diagnosed with fibromyalgia at age 34. My symptoms worsened significantly after the birth of my son.
My son began grinding his teeth at night (bruxism) at age two. The grinding was so loud it would keep my husband and I awake. He developed pains in the bottoms of his feet, and then the middle of his spine. Then, he started developing migraines. By age four, he was diagnosed with Pediatric Fibromyalgia.
So, yes, I believe there is a genetic link to fibromyalgia. Today, my son is a very active, healthy kindergartner, who excels at academics and sports. He is an accelerated, bi-lingual (Dual Immersion) program, (he takes classes in two languages.) We've never treated him like he was "sick," or an "invalid." Fibromyalgia is part of his life, as it is mine, but it does not hold him back.
We both follow the (controversial) Guaifenesin Protocol, and see Dr. R. Paul St. Amand two to three times a year, down in Marina del Ray, CA, (a 1,200 mile round trip drive for us.)I am very careful about who I tell that I have fibromyalgia. I often don't even mention it at doctors' appointments, if I am meeting a new doctor for the first time. Such a stigma attached to the disease. (Otherwise you risk being labeled "pyschosomatic.") So, I have stopped mentioning it and I put down "none" in the medical conditions box.
One day, attitudes may change, and perhaps I can then be fully honest about having fibromyalgia. But, first, I have to be able to "prove" I have this disease. Any chance of you researchers being able to come up with a blood test for fibromyalgia? Apparently, one does not have a "real" disease until you can back it up with a blood test. You're forever stuck in the hypochondriac category until then.
Regards,
Diana
I do keep a blog about fibromyalgia, aimed at others with fibro, and a second blog about pediatric fibro. Both are on my family website, (nothing commercial, no ads,) www.surfercouple.com.)